Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

Diabetologia. 2013 Aug;56(8):1792-801. doi: 10.1007/s00125-013-2931-z. Epub 2013 May 12.

Abstract

Aims/hypothesis: Alterations in white adipose tissue (WAT) function, including changes in protein (adipokine) secretion and extracellular matrix (ECM) composition, promote an insulin-resistant state. We set out to identify novel adipokines regulated by body fat mass in human subcutaneous WAT with potential roles in adipose function.

Methods: Adipose transcriptome data and secretome profiles from conditions with increased/decreased WAT mass were combined. WAT donors were predominantly women. In vitro effects were assessed using recombinant protein. Results were confirmed by quantitative PCR/ELISA, metabolic assays and immunochemistry in human WAT and adipocytes.

Results: We identified a hitherto uncharacterised adipokine, semaphorin 3C (SEMA3C), the expression of which correlated significantly with body weight, insulin resistance (HOMA of insulin resistance [HOMAIR], and the rate constant for the insulin tolerance test [KITT]) and adipose tissue morphology (hypertrophy vs hyperplasia). SEMA3C was primarily found in mature adipocytes and had no direct effect on human adipocyte differentiation, lipolysis, glucose transport or the expression of β-oxidation genes. This could in part be explained by the significant downregulation of its cognate receptors during adipogenesis. In contrast, in pre-adipocytes, SEMA3C increased the production/secretion of several ECM components (fibronectin, elastin and collagen I) and matricellular factors (connective tissue growth factor, IL6 and transforming growth factor-β1). Furthermore, the expression of SEMA3C in human WAT correlated positively with the degree of fibrosis in WAT.

Conclusions/interpretation: SEMA3C is a novel adipokine regulated by weight changes. The correlation with WAT hypertrophy and fibrosis in vivo, as well as its effects on ECM production in human pre-adipocytes in vitro, together suggest that SEMA3C constitutes an adipocyte-derived paracrine signal that influences ECM composition and may play a pathophysiological role in human WAT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / genetics
  • Adipokines / metabolism*
  • Adipose Tissue, White / metabolism
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Matrix / metabolism*
  • Fluorescent Antibody Technique
  • Humans
  • Immunohistochemistry
  • Microscopy, Confocal
  • Semaphorins / genetics
  • Semaphorins / metabolism*

Substances

  • Adipokines
  • Sema3C protein, human
  • Semaphorins